Key Research activity:
1. DNA Topoisomerase structure, cellular and biochemical functions.
2. Explore the molecular mechanisms of DNA damage induced by covalent trapping of Top1 on DNA (Top1cc) and Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediated DNA repair.
3. Explore new DNA repair pathways in mitochondria and the role of mtDNA damage in human diseases.
4. Explore the role of post-translational modifications (PTMs i.e. phosphorylation, acetylation, methylation, ubiquitylation and SUMOylation) of DNA repair proteins and response to anticancer agents.
5. Unravel the functional and biological coupling of Poly(ADP-ribose)polymerase (PARP1) with DNA repair pathways.
6. Explore the molecular mechanism of PARP inhibitors in cancer treatment.
7. Anticancer Drug Discovery: Targeting DNA Topoisomerase with small molecules inhibitors in human cancer.
Wellcome Trust/ DBT India alliance webpage: https://www.indiaalliance.org/fellowsprofile/dr-benu-brata-das-185
Genomic instability leads to cancer, premature aging, neurodegeneration and several human diseases. Other than the nuclear genome, mitochondria also harbor the small, circular DNA (mtDNA) that is essential for life. Mitochondrial reactive oxygen species (ROS) is the source for the endogenous DNA damage.
DNA-repair systems provide a critical defense mechanism against exogenous DNA-damaging agents, such as the human carcinogen, and endogenous sources such as ROS (reactive oxygen species) generated from normal cellular metabolism. This damage includes SSBs (single-strand breaks), DSBs (double-strand breaks) as well as chemical modifications of the bases and sugars. To avoid the deleterious consequences of damage accumulation, cells have developed DNA damage response (DDR) pathways. In recent years it has become apparent that the cellular DDR is a rich signaling network. In addition to DNA repair per se, this network activates cell cycle checkpoints and modulates numerous cellular processes while the damage is being repaired. DNA damage induces post-translational modifications (PTMs i.e. phosphorylation, acetylation, methylation, ubiquitylation and SUMOylation) of histones and non-histone proteins to coordinate chromatin organization and genome maintenance.
Our laboratory primarily focuses on DNA topoisomerases, Top1 is essential in higher eukaryotes as it relaxes positive DNA supercoiling in advance of replication forks and transcription complexes as well as negative supercoiling behind such complexes. DNA topoisomerase I (Top1) regulate DNA supercoiling both in the nucleus and mitochondria to enable faithful transmission of our genetic information to the offspring. However, Top1 are toxic when trapped on the DNA (Top1 cleavage complexes; Top1cc) in the presence of anticancer drug camptothecin or endogenous DNA damage generated by reactive oxygen species (ROS). A key repair enzyme for Top1cc is tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyzes the phosphodiester bond between the DNA 3'-end and the Top1 tyrosyl moiety. Active site mutation of TDP1 causes the severe neurodegenerative syndrome spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 repairs Top1cc by forming complexes with the DNA single stranded break repair enzymes like PARP1-XRCC1-PNKP-Polymerase beta-ligaseIII. Top1cc also generates DNA double-strand breaks, and induces phosphorylated TDP1, H2AX and Chk2 nuclear foci by activation of ATM. Therefore, Top1cc-induced DNA damage response is a complex signaling network and is not fully understood. To unravel the complexity of this signaling network in mechanistic detail and to identify new regulators and novel post-translational modifications of proteins essential for genome maintenance. We will also explore the potential role of mitochondrial DNA (mtDNA) damage, dynamics and metabolism in the pathological-etiology of SCAN1 and related genetic disorders. Thus, our group at IACS is focused to understand how new genes and novel post-translational modifications coordinate the DSBs repair signaling in cells, which can eventually pave the pathway into therapeutic benefit.
We will address our questions using cutting-edge tools of molecular and cellular biology with special emphasis on live-cell microscopy followed by photo bleaching (FRAP assays), gene knockdown using RNAi technology, DNA damage evaluation in single cell by gamma-H2AX staining and Comet assays.
Our recent papers:
31. Invited lecture at the American Catholic University, Washington DC, USA, Department of Biological Sciences, September 10th, 2018. Title: New Challenges in personalised cancer Chemotherapy.
30. Invited Lecture at the Centre of Gene regulation in Health and Disease at Cleveland State University (CSU), Cleveland, OH, USA dated 28th August, 2018. Title: New regulators of DNA Topoisomerase 1-induced DNA damage and Repair.
29.Invited lecture at the DNA Topoisomerases in Biology and Medicine Gordon Research Conference July 29 - August 3, 2018, Mount Holyoke College, MA, USA, Title of the talk: “PRMT5-Mediated Arginine Methylation of TDP1 for the Repair of Topoisomerase I Covalent Complexes"
28. Invited lecture at Indo-Israel meeting organized by INSA India. Recent Advances in Molcular genetics, Feb 12-13; 2018 Title of Talk: New regulators of DNA Topoisomerase I-induced DNA damage and repair.
27. IABS 2018 at IACS Kolkata, 1-3 rd Feb 2018; Title of Talk: New regulators of DNA Topoisomerase I-induced DNA damage and repair
26. Frontiers in Modern Biology, IISER, Kolkata dated January 19-21, 2018; Title of the lecture: New regulators of DNA Topoisomerase I-induced DNA damage and repair
25. Invited lecture at the Department of Molecular Genetics, ERASMUS MC medical school, Rotterdam, NETHERLANDS, Sept 21, 2017. Title of Talk: Role of PARP inhibitors in combination with Top1 inhibitors in cancer
24.EMBO Topoisomerase meeting at Les Diablerets, Switzerland, September 17-20, 2017: Presentation Title: Role of PARP inhibitors in combination with Top1 inhibitors in cancer
23. International meeting: Chromosome Stability 2016, between 15 – 18 December, 2016 in Trivandrum, Kerala, India. Invited lecture : New regulators of DNA Topoisomerase I-induced DNA damage and repair".http://conference.iisertvm.ac.in/chromosome_stability/index.php/pages/speakers
22. ISA visiting professor honorary lecture, Institute of Advances Sciences, University of Bologna, Scuola Superiore di Studi Umanistici, via Marsala 26, Bologna, Italy NOV 08, 2016, FROM 05:30 PM TO 07:30 PM, Title: Targeting DNA topoisomerase in cancer: why so fascinating?" http://www.isa.unibo.it/en/lectures/lecture-by-benu-brata-das
21. University of Bologna, Department of Pharmacia and Biotechnology, Italy. Invited lecture on 28/10/2016 DALLE 14:30 ALLE 16:30, Dove Aula 1, Via Belmeloro 6. Title of The talk: DNA TOPOISOMERASE IN LIFE AND DEATH: NEW therapeutic opportunities ARE ON THE HORIZON" http://www.fabit.unibo.it/it/eventi/copy24_of_i-seminari-del-fabit-1
20: BITS-PILANI Conference on Gene and Genome Regulation (BCGGR-2016), BITS, PILANI, Rajasthan. 18th to 20th, February, 2016. Title of Talk: "DNA Topoisomerase in life and Death: New therapeutic opportunities are on the horizon".
19: BITS, Goa Conference: New Frontiers in Chemistry- from Fundamentals to Applications (NFCFA 2015) during Dec 18th-19th 2015 in Goa. Title of Talk: "DNA Topoisomerase in life and Death: New therapeutic opportunities are on the horizon".
18. EMBO Meeting and workshop: DNA topoisomerases, DNA topology and human health, 13th-17th September 2015, Les Diablerets, Switzerland. Presentation title: “Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells”
17. National Symposium: " Molecules to system" at Presidency University, Kolkata, 29th-31st January, 2014. Invited lecture: "Coupling PARP1 and TDP1 repair pathways: New therapeutic opportunities are on the horizon" .
16. Chromosome Instability 2014: JNCASR Bangalore, India, 14-18th December, 2014. Invited lecture : "Coupling PARP1 and TDP1 repair pathways: New therapeutic opportunities are on the horizon".
15. Gordon Research Conference : DNA Topoisomerase in Biology and Medicine: 10-15 September, 2014 at Sunday River Resort in Newry ME United States. Presentation title: Coupling of Poly(ADP-ribose) polymerase (PARP1) and Tyrosyl-DNA phosphodiesterase ( TDP1) for the repair of Topoisomerase I-induced DNA damage.
14. Gordon Research Conference : DNA, Damage, Mutation & Cancer: March 16-21st, 2014 at the Ventura Beach Marriott, Ventura, California. Presentation title: Coupling of Poly(ADP-ribose) polymerase (PARP1) and Tyrosyl-DNA phosphodiesterase ( TDP1) for the repair of Topoisomerase I-induced DNA damage.
13. UGC-DRS Sponsored National Seminar on “Bioprospecting of Natural Products” scheduled at the Department of Zoology, The University of Burdwan during December 05-06, 2013. Title of talk: DNA Topoisomerase in Life and Death.
12. Gordon Research Conference: A Delicate Balance: Cellular Mutation Pathways in Genetic Stability and Disease at Newport, RI, USA Sep, 2012 Title of talk: “PARP1 is a critical cofactor for TDP1 repair function”.
11. National Cancer Institute Outstanding Postdoctoral Fellow award talk. January 2012, Selected among top five finalists for outstanding fellow at NCI/NIH. Title: “Novel role of TDP1 in the repair of Nuclear and Mitochondrial DNA: Implications in human diseases”.
10. Cold Spring Harbor meeting: Eukaryotic DNA Replication & Genome Maintenance meeting Cold Spring Harbor, NY, USA, September 2011. Title: “Coupling of Poly(ADP-ribose) polymerase (PARP1) and Tyrosyl-DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I (Top1)-mediated DNA damage.
9. Indian Institute of Science Education and Research, Mohali. Title: Novel role of DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria, India. November 2011.
8. Indian Institute of Technology-Bombay. Department of Biotechnology; Title: Novel role of DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria, India. November 2011.
7. Indian Institute of Science Education and Research, Kolkata. Title: Novel role of DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria, India. November 2011.
6. The Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India. Title: Novel role of DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria. Mohanpur, Nodia, India. November 2011.
5. 8th Young Investigator meeting Boston October, 2011 at the Stata Auditorium, MIT, Cambridge, MA, USA. Title: “A Novel Nuclear and Mitochondrial DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1): Insights into Topoisomerase1-induced DNA Damage and Human diseases”
4. 11th Annual Fellows and Young Investigators Colloquium at Williamsburg Marriott hotel from February 25, 2011. Title: Role of Tyrosyl-DNA phosphodiesterase (TDP1) in mitochondrial DNA repair.
3. Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Department of Carcinogenesis, Biomarker and Epidimology. Washington DC 20057. Title: ATM and/or DNA-PK facilitates repair of Topoisomerase I-associated DNA breaks by Novel phosphorylation of TDP1 at Serine 81. October 22, 2009.
2. NDDO Honorary Lecture: ATM and/or DNA-PK facilitates repair of Topoisomerase I-associated DNA breaks by Novel phosphorylation of TDP1 at Serine 81. 8th International Symposium on Targeted Anticancer Therapies 2010, March 4-6. Washington DC, USA.
1. 8th Annual Fellows and Young Investigators Colloquium at Ocean City MD from March 3-5, 2008. Title: DNA Damage induces phosphorylation at Ser81 of the DNA repair enzyme Tyrosyl-DNA phosphodiesterase (TDP1): Exploring its implication in DNA repair.